Skip to main content

What do we know and not know about mirabegron, a novel β3 agonist, in the treatment of overactive bladder?

Abstract

Introduction and hypothesis

Mirabegron is a novel β3-adrenoceptor agonist recently approved by Japanese, American, and European authorities for overactive bladder (OAB) therapy. Here we review existing knowledge on this new class of medication, analyze existing literature on the topic, and make recommendations regarding its administration and necessary future studies.

Methods

We reviewed the current literature and analyzed mirabegron efficacy, safety, and suitability for treating OAB symptoms. We performed a systematic search of Medline/PubMed, and Embase. Studies exploring mechanisms involved in the effects of mirabegron were included. Searches were limited to the English language.

Results

Two phase II and two large-scale phase III multinational randomized controlled trials have supported mirabegron efficacy and tolerability with up to 12 weeks of therapy in OAB patients. The reported frequency and severity of treatment-emergent and serious adverse events were similar to antimuscarinics but with more than threefold lower incidence of dry mouth than with tolterodine. However, effects on the cardiovascular system, cognitive functions, pharmacokinetic interactions with other drugs, and long-term adverse events have not yet been fully investigated.

Conclusion

Anticholinergic drugs should remain the first-line pharmacologic treatment for OAB until head-to-head comparative study eventually shows that mirabegron has equivalent or superior efficacy. However, it seems logical to use mirabegron as second-line treatment of OAB in patients who are poor responders or intolerant to anticholinergics.

This is a preview of subscription content, access via your institution.

References

  1. Haylen BT, de Ridder D, Freeman RM, Swift SE, Berghmans B, Lee J, Monga A, Petri E, Rizk DE, Sand PK, Schaer GN (2010) An International Urogynecological Association (IUGA)/International Continence Society (ICS) joint report on the terminology for female pelvic floor dysfunction. Int Urogynecol J 21(1):5–26

    PubMed  Article  Google Scholar 

  2. Irwin DE, Milsom I, Hunskaar S, Coyne K, Kelleher C, Hampel C et al (2006) Population-based survey of urinary incontinence, overactive bladder, and other lower urinary tract symptoms in five countries: results of the EPIC study. Eur Urol 50:1306–1314

    PubMed  Article  Google Scholar 

  3. Coyne KS, Sexton CC, Kopp ZS, Ebel-Bitoun C, Milsom I, Chapple C (2011) The impact of overactive bladder on mental health, work productivity and health-related quality of life in the UK and Sweden: results from EpiLUTS. BJU Int 108:1459–1471

    PubMed  Article  Google Scholar 

  4. Murphy AM, Krlin RM, Goldman HB (2013) Treatment of overactive bladder: what is on the horizon? Int Urogynecol J 24(1):5–13

    PubMed  Article  Google Scholar 

  5. Andersson KE (1993) Pharmacology of lower urinary tract smooth muscles and penile erectile tissues. Pharmacol Rev 45:253–308

    Google Scholar 

  6. Michel MC, Vrydag W (2006) Alpha1-, alpha2- and beta-adrenoceptors in the urinary bladder, urethra and prostate. Br J Pharmacol 147(Suppl 2):S88–S119

    CAS  PubMed  Article  Google Scholar 

  7. Andersson KE, Arner A (2004) Urinary bladder contraction and relaxation: physiology and pathophysiology. Physiol Rev 84:935–986

    CAS  PubMed  Article  Google Scholar 

  8. Otsuka A, Shinbo H, Matsumoto R, Kurita Y, Ozono S (2008) Expression and functional role of beta-adrenoceptors in the human urinary bladder urothelium. Naunyn Schmiedebergs Arch Pharmacol 377:473–481

    CAS  PubMed  Article  Google Scholar 

  9. Igawa Y, Yamazaki Y, Takeda H et al (1999) Functional and molecular biological evidence for a possible beta3-adrenoceptor in the human detrusor muscle. Br J Pharmacol 126:819–825

    CAS  PubMed  Article  Google Scholar 

  10. Badawi JK, Seja T, Uecelehan H, Honeck P, Kwon ST, Bross S et al (2007) Relaxation of human detrusor muscle by selective beta-2 and beta-3 agonists and endogenous catecholamines. Urology 69:785–790

    PubMed  Article  Google Scholar 

  11. Leon LA, Hoffman BE, Gardner SD, Laping NJ, Evans C, Lashinger ES et al (2008) Effects of the beta 3-adrenergic receptor agonist disodium 5-[(2R)-2-[[(2R)-2-(3-chlorophenyl)-2-hydroxyethyl]amino]propyl],3-benzodioxole-2,2-dicarboxylate (CL-316243) on bladder micturition reflex in spontaneously hypertensive rats. J Pharmacol Exp Ther 326:178–185

    CAS  PubMed  Article  Google Scholar 

  12. Uchida H, Shishido K, Nomiya M, Yamaguchi O (2005) Involvement of cyclic AMP-dependent and -independent mechanisms in the relaxation of rat detrusor muscle via beta-adrenoceptors. Eur J Pharmacol 518:195–202

    CAS  PubMed  Article  Google Scholar 

  13. Frazier EP, Peters SL, Braverman AS, Ruggieri MR Sr, Michel MC (2008) Signal transduction underlying the control of urinary bladder smooth muscle tone by muscarinic receptors and beta-adrenoceptors. Naunyn Schmiedebergs Arch Pharmacol 377:449–462

    CAS  PubMed Central  PubMed  Article  Google Scholar 

  14. Takemoto J, Masumiya H, Nunoki K, Sato T, Nakagawa H, Ikeda Y et al (2008) Potentiation of potassium currents by beta-adrenoceptor agonists in human urinary bladder smooth muscle cells: a possible electrical mechanism of relaxation. Pharmacology 81:251–258

    CAS  PubMed  Article  Google Scholar 

  15. Hristov KL, Cui X, Brown SM, Liu L, Kellett WF, Petkov GV et al (2008) Stimulation of beta3-adrenoceptors relaxes rat urinary bladder smooth muscle via activation of the large-conductance Ca2+ − activated K+ channels. Am J Physiol Cell Physiol 295:1344–1353

    Article  Google Scholar 

  16. Takasu T, Ukai M, Sato S, Matsui T, Nagase I, Maruyama T et al (2007) Effect of (R)-[2-(2-aminothiazol-4-yl)-4′-2-[(2 hydroxy-2-phenylethyl)-amino]ethyl] acetanilide (YM178), a novel selective beta3 adrenoceptor agonist, on bladder function. J Pharmacol Exp Ther 321:642–647

    CAS  PubMed  Article  Google Scholar 

  17. Noguchi Y, Someya A, Ukai M (2009) Effects of mirabegron (YM178) on non-micturition contractions in the bladder of conscious rats with bladder outlet obstruction (BOO). J Urol [proceedings of Annual Meeting of the American Urological Association (AUA) (April 25–30, 2009, Chicago)] 181(4, Suppl.): Abstract 25

  18. Gillespie J, Guilloteau V, Korstanje C, Lluel P, Palea S (2012) Modulation of non-voiding activity by the muscarinergic antagonist tolterodine and the β(3)-adrenoceptor agonist mirabegron in conscious rats with partial outflow obstruction. BJU Int 110(2 Pt 2):E132–E142

    CAS  PubMed  Article  Google Scholar 

  19. Someya A, Ukai M, Yanai H (2010) Mirabegron (YM178), a novel beta3-adrenoceptor (AR) agonist, increased functional bladder capacity and decreased micturition frequency in conscious water-loaded cynomolgus monkeys. Eur Urol Suppl [Proceedings of 25th Congress of the European Association of Urologists (April 16–20, 2010, Barcelona)] 9(2): Abstract 266

  20. Hicks A, McCafferty GP, Riedel E, Aiyar N, Pullen M, Evans C et al (2007) GW427353 (solabegron), a novel, selective beta3-adrenergic receptor agonist, evokes bladder relaxation and increases micturition reflex threshold in the dog. J Pharmacol Exp Ther 323:202–209

    CAS  PubMed  Article  Google Scholar 

  21. Aizawa N, Homma Y, Igawa Y (2011) Effects of mirabegron (YM178), a novel beta3-adrenoceptor agonist, on the primary bladder afferent activity of the rat. Neurourol Urodyn [Proceedings of 41st Annual Meeting of the International Continence Society (August 29-September 2, 2011, Glasgow)] 30(6): Abstract 154

  22. Ursino MG, Vasina V, Raschi E, Crema F, De Ponti F (2009) The beta3-adrenoceptor as a therapeutic target: current perspectives. Pharmacol Res 59:221–234

    CAS  PubMed  Article  Google Scholar 

  23. Arner P, Hoffstedt J (1999) Adrenoceptor genes in human obesity. J Intern Med 245:667–672

    CAS  PubMed  Article  Google Scholar 

  24. Honda K, Nomiya M, Shishido K (2006) Mutation of beta3-adrenocepor gene: a genetic marker for overactive bladder. Neurourol Urodyn 25(suppl):652

    Google Scholar 

  25. Krauwinkel WJ, van Gelderen EM, Groen MJ, Schaddelee M, de Koning P (2010) An open-label, one-sequence crossover study to evaluate the effect of multiple doses of mirabegron on the pharmacokinetics of the CYP2D6 substrate desipramine in healthy subjects. Clin Pharmacol Ther [Proceedings of 111st Annual Meeting of the American Society of Clinical Pharmacology and Therapeutics (ASCPT) (March 17–20,Atlanta)]; 87(Suppl. 1): Abstract PIII-65

  26. Veltkamp S, Gelderen M, Schaddelee M, Krauwinkel W, Koning P (2009) Clinical study into the pharmacokinetic, pharmacodynamic and safety interaction of the novel beta3-adrenoceptor agonist mirabegron and metformin in healthy subjects. Basic Clin Pharmacol Toxicol [Proceedings of 9th Congress of the European Association of Clinical Pharmacology and Therapeutics (EACPT) (July 12–15, 2009, Edinburgh)]; 105(Suppl. 1): Abstract WP107

  27. Sawamoto T, Lee J, Alak A (2011) Phase I, open-label, drug interaction study to evaluate the effect of multiple doses of ketoconazole on single dose mirabegron (YM178) oral controlled absorption system (OCAS) in healthy adult subjects. Clin Pharmacol Ther [112th Annual Meeting of the American Society of Clinical Pharmacology and Therapeutics (March 2–5, 2011, Dallas)]; 89(Suppl. 1): Abstract PI-43

  28. Sawamoto T, Lee J, Cao Y (2011) Phase I, open-label, drug interaction study to evaluate the effect of repeat doses of rifampin on the single-dose pharmacokinetics of mirabegron (YM178) in healthy adult subjects. Clin Pharmacol Ther [Proceedings of 112th Annual Meeting of the American Society of Clinical Pharmacology and Therapeutics (March 2–5, 2011, Dallas)]; 89(Suppl. 1): Abstract PI-44

  29. Chapple C, Dvorak V, Radziszewski P, Van Kerrebroeck P, Wyndaele JJ, Bosman B, Boerrigter P, Drogendijk T, ridder A, Van Der Putten-Slob I, Yamaguchi O, on behalf of the Dragon Investigator Group (2013) A phase II dose-ranging study of mirabegron in patients with overactive bladder. Int Urogynecol J. Mars 8 (Epub ahead of print)

  30. Khullar V, Amarenco G, Angulo JC, Cambronero J, Hoye K, Milson I et al (2013) Efficacy and tolerability of mirabegron, a β(3)-adrenoceptor agonist, in patients with overactive bladder: results from a European-Australian phase III trial. Euro Urol 63:283–295

    CAS  Article  Google Scholar 

  31. Nitti VW, Auerbach S, Martin N, Calhoun A, Lee M, Herschorn S (2012) Results of a randomized phase III trial of Mirabegron in patients with overactive bladder. J Urol. doi:10.1016/j.juro.2012.10.017 [Epub ahead of print]

    Google Scholar 

  32. Chapple CR, Yamaguchi O, Ridder A (2008) Clinical proof of concept study (Blossom) shows novel 3 adrenoceptor agonist YM178 is effective and well tolerated in the treatment of symptoms of overactive bladder. Eur Urol Suppl 7:239

    Google Scholar 

  33. Andersson KE, Olsgansky B (2007) Treating patients with overactive bladder syndrome with antimuscarinics: heart rate considerations. BJU Int 100:1000–1014

    Google Scholar 

  34. Martin N (2012) Randomised, double-blind, placebo-controlled study to assess the ocular safety of mirabegron in normotensive IOP research subjects. Proceedings of European Urology Association Annual Conference; Paris; Poster AM12-1928: 686

  35. Chancellor M, Boone T (2012) Anticholinergics for overactive bladder therapy: central nervous system effects. CNS Neurosci Ther 18:167–174

    CAS  PubMed  Article  Google Scholar 

  36. Rodriguez M, Carillon C, Coquerel A, Le Fur G, Ferrara P, Caput D et al (1995) Evidence for the presence of beta 3-adrenergic receptor mRNA in the human brain. Brain Res Mol Brain Res 29:369–375

    CAS  PubMed  Article  Google Scholar 

  37. Athanaspoulos A, Chapple C, Fowler C, Gratzke C, Kaplan S, Stief C et al (2011) The role of antimuscarinics in the management of men with symptoms of overactive bladder associated with concomitant bladder outlet obstruction: an update. Eur Urol 60:94–105

    Article  Google Scholar 

  38. Bhide AA, Digesu GA, Fernando R, Khullar V (2012) Use of mirabegron in treating overactive bladder. Int Urogynecol J 23(10):1345–1348

    PubMed  Article  Google Scholar 

Download references

Conflicts of interest

Dr J Corcos: Advisor for Allergan, Astellas, Waston; consultant for Allergan; Investigator for Astellas and Speaker for Allergan

Dr R Caremel: no disclosures

O Loutochin: no disclosures

Author information

Affiliations

Authors

Corresponding author

Correspondence to Jacques Corcos.

Rights and permissions

Reprints and Permissions

About this article

Cite this article

Caremel, R., Loutochin, O. & Corcos, J. What do we know and not know about mirabegron, a novel β3 agonist, in the treatment of overactive bladder?. Int Urogynecol J 25, 165–170 (2014). https://doi.org/10.1007/s00192-013-2161-4

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00192-013-2161-4

Keywords

  • Mirabegron
  • Overactive bladder
  • Urinary incontinence
  • New drug
  • Review